Approximately 5% of Americans have asthma, an inflammatory airway disease whose hallmark is airway hyper-reactivity (AHR). During AHR, bronchial smooth muscles rapidly constrict resulting in airway obstruction. Most patients self-administer inhaled beta2-adrenoceptor (beta2AR) agonists such as salmeterol for relief of this life-threatening event. Unfortunately, chronic administration of beta2AR agonists results in desensitization, in part due to downregulation of the beta2-adrenoceptors. In contrast, upregulation of beta2-adrenoceptors in the lungs of transgenic mice essentially eliminates AHR. The company has data showing that chronic administration of INV102, a beta inverse agonist or 'beta-blocker', also increases beta2-adrenoceptors. It also results in significantly reduced AHR in an allergic asthma mouse model. This suggests that chronic administration of INV102 may prove beneficial to human asthmatics. Since most asthma patients are currently using beta2AR agonists either continuously or on an 'as-needed' basis to relieve asthma attacks, it is important to test whether INV102 can be used in conjunction with this class of drugs. The specific aims of this research proposal are 1) test whether INV102 can be used with the beta2-agonist salbutamol to modify AHR in an allergic asthma rat model and 2) test whether INV102 can be used with salmeterol inhaled twice a day, mimicking asthma patient behavior, to modify AHR in an allergic asthma rat model. The long term objective of these Phase I studies is to translate this research to the clinical setting with a Phase II SBIR to test this novel combination therapy on asthmatic patients to apply for FDA approval.